Oral sustained-release triple layer tablet

ABSTRACT

The present invention relates to an oral sustained-release triple layer tablet, more particularly, a triple layer tablet consisting of an inner immediate-release layer containing a pharmaceutically active ingredient and two outer layers containing swellable polymers. Upon exposure to aqueous media, the two outer layers swell to form gelled layers surrounding the lateral side of the inner layer rapidly, thereby control effectively the release of the pharmaceutically active ingredient from the inner immediate-release layer.

TECHNICAL FIELD

The present invention relates to an oral sustained-release triple layertablet, more particularly, a triple layer tablet consisting of an innerimmediate-release layer containing a pharmaceutically active ingredientand two outer layers containing swellable polymers. On exposure toaqueous media, the two outer layers swell to form gelled layerssurrounding the lateral side of the inner layer rapidly, thereby controleffectively the release of drug from the inner immediate-release layer.

BACKGROUND ART

Oral sustained-release formulation is developed to control the releaseof active ingredient at a designed rate and to obtain its optimal bloodconcentration therapeutically. This property leads to the reduction ofthe administration frequency, which helps to increase patient complianceand prevent adverse effects.

In order to achieve the object, a variety of dosage forms have beendeveloped. Among them, because of simple composition and ease ofmanufacture, many studies have been conducted on a matrix system, inwhich active ingredients are dispersed in polymers which control therelease rate

However, the release from the simple matrix containing water-solublepolymers such as hydroxypropylmethylcellulose is subject to Fickiandiffusion, which causes some drawbacks such as an initial burst.

There have been attempts to introduce an additional release-controllinglayer into the matrix formulation, for the purpose of avoiding aninitial burst and initiating the release of active ingredient after apredetermined time.

U.S. Pat. No. 5,422,123 discloses a tablet consisting of a core and asupport applied to the core to partly cover its surface, in which therelease of pharmaceutically active ingredient is controlled as follows:The core contains the drug and a polymer which swells and gelates uponcontact with aqueous media in a ratio of 1:9 to 9:1, based on the amountof drug, so that the release of pharmaceutically active ingredient iscontrolled by the same mechanism as in the matrix formulation, but thesupport containing a polymer which is slowly soluble or gellable inaqueous media controls the surface area of the core and varies therelease patterns.

U.S. Pat. No. 5,549,913 discloses a multilayer tablet for release ofpharmaceutically active ingredient at a constant rate with a zero orderkinetic profile, in which two outer layers contain pharmaceuticallyactive ingredient and hydrophilic polymers, and an inner layer containsa water-soluble polymer without the pharmaceutically active ingredient.The inner layer is readily dissolved in aqueous media to separate thetwo outer layers, and thus to increase the surface area of the matrix.

U.S. Pat. No. 5,626,874 discloses a multilayer tablet consisting of twoouter layers containing gellable or erodible polymers and an inner layercontaining an active ingredient. The side surface of the inner layeroccupies about 5 to 35% of the tablet's total surface.

U.S. Pat. No. 5,783,212 discloses a multilayer tablet for release ofpharmaceutically active ingredient at a constant rate with a zero orderkinetic profile, in which two outer layers contain swellable anderodible polymers, an inner layer contains a pharmaceutically activeingredient and swellable and erodible polymers, and each layer differsin composition and thickness.

U.S. Pat. No. 6,730,321 discloses a press-coated tablet that facilitatesa pulsatile release of pharmaceutically active ingredient, consisting ofan immediate-release core and a sustained-release layer, which ispress-coated.

In the above prior arts, an immediate-release inner layer containingpharmaceutically active ingredient is not introduced or, even ifintroduced, the immediate-release inner layer is completely coated withthe controlling layers. This is because if the inner layer of the triplelayer tablet does not contain polymers to control the release and isexposed to aqueous media, there will be several problems; namely,excessive initial burst, layer separation due to loss of the innerimmediate-release layer, and significant deviation in release rate,which can be fully predicted by those skilled in the art.

The present inventors have found that surprisingly although an innerimmediate-release layer containing a pharmaceutically active ingredientis not completely coated but contacted with two outer layers, if saidlayers contain swellable polymers, those two outer layers swell to formgelled layers surrounding the lateral side of the inner layer rapidlyupon exposure to aqueous media acting to control the release of activeingredient from the inner immediate-release layer uniformly andreproducibly, thereby completing the present invention.

DISCLOSURE Technical Problem

The object of the present invention is to provide a sustained-releasetriple layer tablet, consisting of an inner immediate-release layercontaining a pharmaceutically active ingredient and two outer layerscontaining swellable polymers. On exposure to aqueous media, the twoouter layers swell to form gelled layers surrounding the lateral side ofthe inner layer, thereby controlling effectively the release of drugfrom the inner immediate-release layer.

Technical Solution

In order to achieve the object, the present invention provides asustained-release triple layer tablet, consisting of an inner layerwhich releases drug immediately by itself and two outer layers whichcontain swellable polymers controlling the release of drug from thetriple-layer tablet.

Advantageous Effects

When the oral sustained-release triple layer tablet according to thepresent invention is exposed to aqueous media, the two outer layersswell to form gelled layers surrounding the lateral side of the innerlayer, thereby effectively controlling the release of pharmaceuticallyactive ingredient from the inner immediate-release layer. The abovetriple layer tablet can reduce an initial burst, one of the drawbacks ofthe matrix, and achieve a variety of release patterns allowing forseveral kinds of sustained-release tablets.

DESCRIPTION OF DRAWINGS

FIG. 1 shows an oral sustained-release triple layer tablet, consistingof an inner immediate-release layer (102) containing a pharmaceuticallyactive ingredient, an upper outer layer (101) and lower outer layer(103) containing swellable polymers;

FIG. 2 shows the results of the stirring and gelling test of Example 1;

FIG. 3 shows the results of the dissolution test of Comparative Examples1 and 2; and

FIG. 4 shows the results of the dissolution test of Examples 3 to 6.

BEST MODE

The triple layer tablet of the present invention is characterized inthat upon exposure to aqueous media, the two outer layers swell to formgelled layers surrounding an inner immediate-release layer, therebycontrolling the release of pharmaceutically active ingredient from theinner layer.

Hereinafter, the sustained-release triple layer tablet according to thepresent invention will be described in more detail.

In the present invention, the inner immediate-release layer is containedin an amount of 5 to 60 w/w %, preferably 10 to 40 w/w %, based on thetotal weight of the tablet.

Examples of the pharmaceutically active ingredient contained in theinner immediate-release layer may include antihypertensives (doxazosinmesylate, terazosin hydrochloride, etc.), anti-benign prostatichyperplasia agents (tamsulosin hydrochloride, etc.), antihyperlipidemics(simvastatin, lovastatin, fluvastatin, etc.), nonsteroidalanti-inflammatory drugs (acetaminophen, zaltoprofen, etc.), analgesicdrugs (tramadol hydrochloride, etc.), antidiabetes drugs, and hypnotics.

It is preferable that, when the dissolution test is performed in aqueousmedia, 80% or more of the pharmaceutically active ingredient is releasedfrom the inner immediate-release layer without the outer layers within 1hour.

In addition to the pharmaceutically active ingredient, the innerimmediate-release layer may further include pharmaceutically acceptableexcipients (e.g., lactose, dextrose, sucrose, dextrate, mannitol,sorbitol, xylitol, sodium chloride, magnesium chloride, calciumphosphate dibasic, citric acid, microcrystalline cellulose, etc.),binders (e.g., copovidone, polyvinylpyrrolidone, hydroxypropylcellulose,etc.), disintegrants (e.g., sodium starch glycolate, croscarmellosesodium, crospovidone, low-substituted hydroxypropylcellulose),lubricants (e.g., magnesium stearate, stearic acid, sodium stearylfumarate, colloidal silicone dioxide, etc.), or the like.

In the present invention, the dissolution media quickly permeates thesustained-release triple layer tablet through the innerimmediate-release layer, and is rapidly supplied to the swellablepolymers of the two outer layers in contact with the inner layer tofacilitate the formation of gelled layers surrounding the inner layer.

In the present invention, the two outer layers contain the swellablepolymer in an amount of 40 to 95 w/w %, preferably 60 to 90 w/w %, basedon the total weight of the tablet. The compositions and amounts of thetwo outer layers may be the same or different from each other, asrequired.

The polymers contained in the two outer layers are swellable uponexposure to aqueous media, and examples thereof may includepolyethyleneoxide, hydroxypropylmethylcellulose, hydroxypropylcellulose,carboxymethylcellulose, polyvinylalcohol, carbomer and so on, preferablypolyethyleneoxide having a viscosity of 400 cps or more (in 2% aqueoussolution) and hydroxypropylmethylcellulose having a viscosity of 4000cps or more (in 2% aqueous solution).

For the purpose of obtaining various dissolution profiles, the two outerlayers may optionally include a pharmaceutically active ingredient. Inan embodiment, the pharmaceutical active ingredient in an outer layermay be the pharmaceutically active ingredient contained in the innerimmediate-release layer.

The two outer layers may additionally include pharmaceuticallyacceptable excipients (e.g., lactose, dextrose, sucrose, dextrate,mannitol, sorbitol, xylitol, sodium chloride, magnesium chloride,calcium phosphate dibasic, citric acid, microcrystalline cellulose),binders (e.g., copovidone, polyvinylpyrrolidone,hydroxypropylcellulose), lubricants (e.g., magnesium stearate, stearicacid, sodium stearyl fumarate, colloidal silicone dioxide), or the like.

In the present invention, when the sustained-release triple layer tabletis exposed to aqueous media, the two outer layers swell to form gelledlayers surrounding the inner immediate-release layer. This effect canprevent an initial burst of pharmaceutically active ingredient from theinner immediate-release layer and ensures that the tablet strength isnot separated into each layer by gastrointestinal motility. Further, thegelled layer becomes a release-controlling membrane, making thesustained release dosage form.

In addition, the present invention provides a method for preparing theoral sustained-release triple layer tablet, comprising the steps of:

mixing the drug and pharmaceutically acceptable additives and optionalgranulating to prepare mixtures for the inner immediate-release layer ofsustained-triple layer tablets;

mixing the swellable polymers, pharmaceutically acceptable additives,and optional drug and optionally granulating to prepare each mixture forthe two outer layers; and tabletting the mixtures in turn.

The above tablets are prepared by a conventional method. That is,ingredients of each layer are mixed using a mixer, and then directlycompressed using a multilayer tabletting machine, or ingredients of eachlayer are mixed to prepare granules using a machine such as a verticalgranulator and a roller compactor, and then compressed to prepare theoral sustained-release triple layer tablet.

MODE FOR INVENTION

Hereinafter, the present invention will be described in more detail withexamples. However, these examples are for the illustrative purpose only,and the invention is not intended to be limited by these examples.

Examples 1 and 2

According to table 1, aqueous pigment (Yellow No. 5), copovidone, anddextrate passed through a 50 mesh sieve were blended for an inner layer,and a swellable polymer such as polyethyleneoxide (commercial name:Polyox WSR Coagulant, Dow Chemicals) or hydroxypropylmethylcellulose(commercial name: Methocel 100M CR, Dow Chemicals) and magnesiumstearate passed through a 30 mesh sieve were blended for two outerlayers. Each mixture was compressed in turn to be a triple layer tabletwith a diameter of 9.0 mm at the final pressure of 6 MPas using ahydraulic press.

TABLE 1 Compositions of Examples 1 and 2 (unit: mg) Layers IngredientsExample 1 Example 2 Upper layer Polyethyleneoxide 99.5 — (Polyox WSRCoagulant ™) Hydroxypropylmethylcellulose — 99.5 (Methocel K100M CR ™)Magnesium stearate 0.5 0.5 Intermediate Yellow No. 5 1.0 1.0 layerDextrate 46.5 46.5 Copovidone 2.5 2.5 Lower layer Polyethylene oxide99.5 — (Polyox WSR Coagulant ™) Hydroxypropyl methylcellulose — 99.5(Methocel K100M CR ™) Magnesium stearate 0.5 0.5 Total 250.0 250.0

Examples 3 to 6

According to table 2, terazosin hydrochloride dihydrate, copovidone, anddextrate or lactose passed through a 50 mesh sieve were blended for aninner layer, and polyethyleneoxide (commercial name: Polyox WSRCoagulant, Dow Chemicals) and magnesium stearate passed through a 30mesh sieve were blended for two outer layers. Each mixture wascompressed in turn to be a triple layer tablet with a diameter of 9.0 mmat the final pressure of 6 MPas using a hydraulic press.

TABLE 2 Compositions of Examples 3 to 6 (unit: mg) Exam- Exam- Exam-Exam- Layers Ingredients ple 3 ple 4 ple 5 ple 6 Upper layerPolyethyleneoxide 99.500 99.500 99.500 99.500 (Polyox WSR Coagulant ™)Magnesium stearate 0.500 0.500 0.500 0.500 Intermediate Terazosin 3.5613.561 3.561 3.561 layer hydrochloride dihydrate Lactose 62.939 24.939 —— Dextrate — — 62.939 24.939 Copovidone 3.500 1.500 3.500 1.500 Lowerlayer Polyethyleneoxide 99.500 99.500 99.500 99.500 (Polyox WSRCoagulant ™) Magnesium stearate 0.500 0.500 0.500 0.500 Total 270.00230.00 270.00 230.00

Examples 7 and 8

According to table 3, a solution of tamsulosin hydrochloride andpovidone K30 dissolved in 4 mg of purified water per tablet was added tolactose, kneaded, dried and granulated. Then, copovidone and dextratepassed through a 50 mesh sieve were blended for an inner layer, andpolyethyleneoxide (commercial name: Polyox WSR Coagulant, Dow Chemicals)and magnesium stearate passed through a 30 mesh sieve were blended fortwo outer layers. Each mixture was compressed in turn to be a triplelayer tablet with a diameter of 9.0 mm at the final pressure of 6 MPasusing a hydraulic press.

TABLE 3 Compositions of Examples 7 and 8 (unit: mg) Layers IngredientsExample 7 Example 8 Upper layer Polyethyleneoxide 99.50 99.50 (PolyoxWSR Coagulant ™) Magnesium stearate 0.50 0.50 Intermediate Tamsulosinhydrochloride 0.40 0.40 layer Povidone K30 1.80 1.80 Lactose 53.60 53.60Copovidone 4.20 7.00 Dextrate — 37.20 Lower layer Polyethyleneoxide99.50 99.50 (Polyox WSR Coagulant ™) Magnesium stearate 0.50 0.50 Total260.00 300.00

Comparative Examples 1 and 2

According to table 4, terazosin hydrochloride dihydrate, copovidone, anddextrate or lactose passed through a 50 mesh sieve were blended toprepare a tabletting composition. The mixture was compressed into atablet with a diameter of 9.0 mm, at the pressure of 6 MPas using ahydraulic press.

TABLE 4 Compositions of Comparative Examples 1 and 2 (unit: mg)Ingredients Comparative Example 1 Comparative Example 2 Terazosin 3.5613.561 hydrochloride dihydrate Lactose 62.939 — Dextrate — 62.939Copovidone 3.500 3.500 Total 70.000 70.000

Comparative Example 3

According to table 5, a solution of tamsulosin hydrochloride andpovidone K30 dissolved in 4 mg of purified water per tablet was added tolactose, kneaded, dried and granulated. After being mixed withcopovidone, the mixture was compressed into a tablet with a diameter of9.0 mm at the pressure of 6 MPas using a hydraulic press

TABLE 5 Composition of Comparative Example 3 (Unit: mg) IngredientsComparative Example 3 Tamsulosin hydrochloride 0.40 Povidone K30 1.80Lactose 53.60 Copovidone 4.20 Total 60.00

Test 1: Stirring and gelling test

A stirring and gelling test for Example 1 was performed to confirmwhether, upon exposure to aqueous media, the triple layer tablet formedgelled layers surrounding the inner layer and whether the layersseparated or not. Stirring was performed in 900 mL of pH 6.8 phosphatebuffer (Korean Pharmacopoeia, disintegration test 2^(nd) solution) usinga magnetic stirrer. The results are shown in FIG. 2.

FIG. 2 shows that the triple layer tablet of Example 1 formed gelledlayers, upon exposure to aqueous media, surrounding the inner layer asthe two outer layers swell. Further, that no layer separation occurredafter stirring for 3 hours provided that the triple layer tablet wasstrong enough to endure gastrointestinal motility and to control therelease of drug from the inner layer. The swollen triple layer tabletafter 3 hours of testing was completely dried in a drier. As shown inthe cross-sectional view, the inner immediate-release layer at initialexposure was surrounded by the two swollen outer layers, and completelyisolated from the dissolution media by a gelled layer.

Test 2: Dissolution test

Dissolution tests for Comparative Examples 1 and 2 and Examples 4 to 7were performed in 900 mL of pH 6.8 phosphate buffer (KoreanPharmacopoeia, disintegration test 2 solution) at 100 rpm using thepaddle method. The results are shown in FIGS. 3 and 4.

Comparative Examples 1 and 2 show tablets composed of the innerimmediate-release layer of a triple layer tablet only wherein 90% ormore of active ingredients were released within 30 min. In contrast, itwas found that since the triple layer tablets of Examples 4 to 7 hadouter layers containing a swellable polymer to control the release onthe upper and lower sides of the inner immediate-release layer, the twoouter layers surrounded the lateral side of the inner immediate-releaselayer to effectively control the release of pharmaceutically activeingredient from the inner layer for about 24 hrs.

The present invention has been described in detail with reference topreferred embodiments thereof. However, it will be appreciated by thoseskilled in the art that changes may be made in these embodiments withoutdeparting from the principles and spirit of the invention, the scope ofwhich is defined in the appended claims and their equivalents.

The invention claimed is:
 1. An oral sustained-release triple-layertablet comprising: an inner immediate-release layer comprising apharmaceutically active ingredient and a binder, and two outer layers,each outer layer comprising a swellable polymer which is polyethyleneoxide having a viscosity of 400 cps or greater in 2% aqueous solution,or hydroxypropyl methylcellulose having a viscosity of 4,000 cps orgreater in 2% aqueous solution, or a mixture of the polyethylene oxideand the hydroxypropyl methylcellulose, wherein the innerimmediate-release layer has an exposed lateral side which is not coveredby the two outer layers, wherein only the two outer layers comprise theswellable polymer, and the two outer layers swell upon exposure toaqueous medium to form gelled layers that surround the exposed lateralside of the inner immediate-release layer, and wherein the two outerlayers comprise 40 to 95% by weight of the swellable polymer, based onthe total weight of the tablet.
 2. The oral sustained-release triplelayer tablet of claim 1, wherein the inner immediate-release layer ischaracterized during dissolution testing in an aqueous medium such that80% or more of the pharmaceutically active ingredient is released fromthe inner immediate-release layer without the outer layers within onehour from exposure to the aqueous medium.
 3. The oral sustained-releasetriple layer tablet of claim 1, wherein the inner immediate-releaselayer further comprises a pharmaceutically acceptable excipient.
 4. Theoral sustained-release triple layer tablet of claim 1, wherein thepharmaceutically active ingredient is selected from the group consistingof doxazosin, terazosin, tamsulosin, simvastatin, lovastatin,fluvastatin, acetaminophen, zaltoprofen and tramadol.
 5. The oralsustained-release triple layer tablet of claim 3, wherein thepharmaceutically active ingredient is terazosin or tamsulosin.
 6. Theoral sustained-release triple layer tablet of claim 1, wherein the twoouter layers containing the swellable polymer include a pharmaceuticallyacceptable excipient, binder, disintegrant or lubricant.
 7. The oralsustained-release triple layer tablet of claim 1, wherein each of thetwo outer layers containing the swellable polymer include apharmaceutically active ingredient.
 8. The oral sustained-release triplelayer tablet of claim 1, wherein the inner immediate-release layer isincluded in an amount of 5 to 60% by weight, based on the total weightof the tablet.
 9. The oral sustained-release triple layer tablet ofclaim 8, wherein the two outer layers comprise 60 to 90% by weight ofthe swellable polymer, based on the total weight of the tablet.
 10. Anoral sustained-release triple-layer tablet comprising: an innerimmediate-release layer comprising a pharmaceutically active ingredientand a binder, wherein the pharmaceutical active ingredient is selectedfrom the group consisting of doxazosin, terazosin, tamsulosin,simvastatin, lovastatin, fluvastatin, acetaminophen, zaltoprofen andtramadol, and two outer layers comprising polyethylene oxide having aviscosity of 400 cps or greater in 2% aqueous solution, wherein theinner immediate-release layer is characterized during dissolutiontesting in an aqueous medium such that 80% or more of thepharmaceutically active ingredient is released from the innerimmediate-release layer without the outer layers within one hour fromexposure to the aqueous medium, wherein the inner immediate-releaselayer has an exposed lateral side which is not covered by the two outerlayers, wherein only the two outer layers comprise the polyethyleneoxide, and the two outer layers swell upon exposure to aqueous medium toform gelled layers that surround the exposed lateral side of the innerimmediate-release layer, and wherein the oral sustained-releasetriple-layer tablet comprises 5 to 60% by weight of the innerimmediate-release layer and 40 to 95% by weight of the polyethyleneoxide, based on the total weight of the tablet.
 11. The oralsustained-release triple layer tablet of claim 1, wherein the swellablepolymer of at least one of the two outer layers comprises thepolyethylene oxide.
 12. The oral sustained-release triple-layer tabletof claim 10, wherein the inner immediate-release layer further comprisesa pharmaceutical acceptable excipient.
 13. An oral sustained-releasetriple-layer tablet comprising: an inner immediate-release layercomprising a pharmaceutically active ingredient and a binder, whereinthe pharmaceutical active ingredient is selected from the groupconsisting of doxazosin, terazosin, tamsulosin, simvastatin, lovastatin,fluvastatin, acetaminophen, zaltoprofen and tramadol, and two outerlayers comprising polyethylene oxide having a viscosity of 400 cps orgreater in 2% aqueous solution, wherein the inner immediate-releaselayer is characterized during dissolution testing in an aqueous mediumsuch that 80% or more of the pharmaceutically active ingredient isreleased from the inner immediate-release layer without the outer layerswithin one hour from exposure to the aqueous medium, wherein the innerimmediate-release layer has an exposed lateral side which is not coveredby the two outer layers, wherein the two outer layers swell uponexposure to aqueous medium to form gelled layers that surround theexposed lateral side of the inner immediate-release layer, and whereinthe oral sustained-release triple-layer tablet comprises 5 to 60% byweight of the inner immediate-release layer and 40 to 95% by weight ofthe polyethylene oxide, based on the total weight of the tablet.
 14. Theoral sustained-release triple-layer tablet of claim 13, wherein theinner immediate-release layer further comprises a pharmaceuticalacceptable excipient.
 15. An oral sustained-release triple-layer tabletcomprising: an inner immediate-release layer comprising apharmaceutically active ingredient, a pharmaceutical acceptable diluentand a binder, and two outer layers, each outer layer comprising aswellable polymer which is polyethylene oxide having a viscosity of 400cps or greater in 2% aqueous solution, or hydroxypropyl methylcellulosehaving a viscosity of 4,000 cps or greater in 2% aqueous solution, or amixture of the polyethylene oxide and the hydroxypropyl methylcellulose,wherein the inner immediate-release layer is characterized duringdissolution testing in an aqueous medium such that 80% or more of thepharmaceutically active ingredient is released from the innerimmediate-release layer without the outer layers within one hour fromexposure to the aqueous medium, wherein the inner immediate-releaselayer has an exposed lateral side which is not covered by the two outerlayers, wherein the two outer layers swell upon exposure to aqueousmedium to form gelled layers that surround the exposed lateral side ofthe inner immediate-release layer, and wherein the two outer layerscomprise 40 to 95% by weight of the swellable polymer, based on thetotal weight of the tablet.
 16. The oral sustained-release triple-layertablet of claim 15, wherein the inner immediate-release layer furthercomprises a pharmaceutical acceptable excipient.